Advances in HIV management over the past 20 years have been striking. HIV-infected people receiving one of the many effective and available antiretroviral therapy (ART) regimens can achieve near-normal life expectancy. Despite this progress, nearly three-quarters of those with HIV infection in the US fail to realize the benefits f ART because they have not been tested, linked to and retained in care, or maintained on suppressive therapy. Together, these problems define the challenge of the HIV cascade of care; attrition in any area compromises individual health and leads to further HIV transmission. For those whose HIV is successfully treated, comorbidities, often related to tobacco use and depression, are major contributors to poor outcomes. Important clinical policy questions remain unanswered in all of these areas, and are particularly challenging in the face of increasingly limited resources for HIV care in the US. Beginning in 1997, NIAID has supported our research group in developing and expanding the Cost- Effectiveness of Preventing AIDS Complications (CEPAC) US Model, a computer simulation of the natural history, clinical management, outcomes, costs, and cost-effectiveness of HIV testing and treatment in the United States. This support was continued in 2001 and awarded R37 MERIT status in 2005, with continuation of that MERIT support in 2009. In the last five year cycle, the collaboration produced 27 original papers in peer-reviewed journals, with an additional five manuscripts submitted. In this competing continuation, we propose to expand upon the CEPAC US model, adding innovative modeling methodology and novel applications to address critical questions in HIV/AIDS care. We have three aims: Specific Aim 1: To assess the cost-effectiveness and budget impact of novel antiretroviral therapies for HIV-infected patients in care. Specific Aim 2: To determine the clinical impact, cost, and cost-effectiveness of strategies to increase the number of HIV-infected people entering and receiving effective care in the US. Specific Aim 3: To determine the outcomes and cost-effectiveness of interventions to reduce morbidity from smoking and depression in HIV-infected persons in the US. Our internationally-recognized, multidisciplinary team has an established record of producing leading, high-impact publications and advancing the methods of cost-effectiveness analysis in HIV research. This research has informed HIV care and guidelines, both in the US and internationally. By leveraging the team's achievements over past years and accomplishing the aims described above, the proposed studies clearly align with the 2014 research priorities of the NIH Office of AIDS Research to improve disease outcomes for people living with HIV and to reduce new infections in the US. This work will address critical HIV clinical research and policy questions in the United States over the next five years.